Anti-acid pharmaceutical composition in powder form and process for making it

ABSTRACT

An anti-acid pharmaceutical composition for the rapid and prolonged neutralization of gastric acidity with mucosa-protecting activity in powder form to prepare, by dispersion in water, a pharmaceutical solution or suspension for oral use characterized in that the composition includes sodium alginate; an anti-acid soluble agent or a combination of anti-acids; an inhibitor of proton pump; diluent and sweetening agents, wherein a) at least 30% of sodium alginate present in the formulation along with the total of the inhibitor of proton pump are homogeneously distributed over the surface of the total soluble anti-acid agent or of the combination of anti-acids of the composition; and b) the rest, about 70%, of sodium alginate present in the formulation contains a percentage of humidity of less than 2%.

FIELD OF THE INVENTION

The present invention refers to a pharmaceutical composition for oraluse and a process for making it containing sodium alginate, a protonpump inhibitor y and one or more soluble or partially soluble anti-acidsfor the treatment of hyperacidity with immediate or long lastingtherapeutic activity.

BACKGROUND

Hyperacidity is an entity which is present in various digestive tractpathologic states. In each case it appears with proper intensity,duration and characteristics. It is present in the case of gastriculcer, gastroesophagic reflux, erosive esophagitis, pathologichypersecretion such as Zollinger-Ellison syndrome, duodenal erosions orgastric ulcers associated with the administration of non-steroidalanti-inflammatory drugs, infection due to Helicobacter pylori, ulcer dueto stress (Dollery, Colin et al.; Therapeutic Drugs Vol. 2; Edic.Churchill Livingstone, UK, 1991), which is incorporated by referenceherein in its entirety), consumption of substances harmful to thedigestive apparatus (for example, coffee, alcohol, and the like).

The hyperacidity caused by the abnormal or excessive production of acidresults in inflammation of the stomach or gastritis. It also results inesophagic involvement when it produces reflux from the stomach to theesophagus.

Numerous drugs have shown to be effective for controlling or suppresshyperacidity as a symptom.

Such drugs have particular characteristics regarding behavior,efficiency and duration of action.

Thus, for example:

1. Anti-acids:

Are generally inorganic soluble or little soluble salts, alone or incombination. Among them are: calcium and magnesium carbonate, sodiumbicarbonate, aluminum hydroxide, aluminum phosphate, and the like.

After their entering into the stomach they neutralize immediatelygastric acidity. They act in situ and do not require prior absorption.

They have an immediate therapeutic effect though they are short acting.

2. Alginic acid and its sodium and magnesium salts:

The alginic acid and its salts associates with sodium and potassiumbicarbonate have shown that, after entering the stomach environment theyform a viscous suspension (or a gel) exerting protecting activity overgastric mucosa. The scientific and patent literature on its activity iswide. Thus, for example:

-   Mandel K. G.; Daggy B. P.; Brodie D. A; Jacoby, H. L., 2000. Review    article: Alginate-raft formulations in the treatment of heartburn    and acid reflux. Aliment. Pharmacol. Ther. 14 669-690[.], which is    incorporated by reference herein in its entirety;-   Bioadhesive oesophageal bandages: protection against acid and pepsin    injury. Man Tang, Peter Dettmar, Hannah Batchelor—International    Journal of Pharmaceutics 292 (2005)—169-177, which is incorporated    by reference herein in its entirety.

The number of commercially available alginate products for therapeuticuse worldwide is also important. Thus, for example, in MIMS (MonthlyIndex of Medical Specialities) of Great Britain there are mentioned somepharmaceutical products containing sodium alginate and potassiumbicarbonate (Gaviscon Advance) for heat, esophagic reflux and dyspepsia,Liquid Gaviscon containing sodium alginate, sodium bicarbonate andcalcium carbonate. There is also a composition formed by sodium andmagnesium alginate (Gaviscon Infant).

3. Antagonists of H2 Histamine receptors:

They reduce the production of histamine which stimulates the formationof acid in the stomach due to the selective blockade of H₂ receptors.

Compared with prior art anti-acids, they have longer effect and durationof action (6 to 12 hours) (Goodman y Gilman. Las bases farmacológicas dela terapéutica; Vol I, pá. 1025, X Edición, Mc. Graw Hill, 2003), whichis incorporated herein by reference in its entirety.

Preferred examples are: cimetidine, nizatidine, famotidine andranitidine.

4. Inhibitors of proton pump:

This is the most modern pharmacologic group for this kind oftherapeutics. They act by selectively and specifically blocking theH⁺-K⁺⁻-ATPase enzyme of stomach parietal cell. They cause a markedreduction of the production of acid by the stomach parietal cells.

Thus, for example, in patients with duodenal ulcer, oral administrationof 20 mg of omeprazole keeps the gastric pH in 3 or greater than 3 for17 hours. The maximum effect is reached within 4 days of treatment.

Preferred examples are: omeprazole, lansoprazole, esomeprazole,pantoprazole, rabeprazole and the like.

The use of each one of the above mentioned alternatives is associatedwith the specific characteristic and intensity of the disease statecausing hyperacidity.

Anti-acids and alginates have shown immediate effect as they act in thestomach and do not require prior absorption. The control of hyperacidityis rapid but with short duration.

On the other hand, the inhibitors of proton pump do not have immediateeffect. Their effect is long because they necessarily have to beabsorbed in order to exert their activity. Thus, for example, theabsorption of omeprazole is done in the small intestine and is completedby 3-6 hours. Such a behavior causes some technical inconveniencies forthe design of a pharmaceutical composition. Since:

a) Omeprazole requires, in fasting state, at least 20 to 30 minutes toreach the intestine.

b) It also requires an additional time for its intestinal absorption.

c) Since it is a scarcely stable substance in acid medium, while it isin the gastric environment, it is easily destructed before it reachesthe intestine and, therefore, it should necessarily be protected fromsaid gastric acidity.

The low stability of omeprazole in an acid medium has been widelydocumented from 1985 (Pilbrant and Cederberg—SCAND. J GASTROENTEROLOGY(1985), 20 (Suppl. 108)—p. 113-120) (Lindberg Per et al.—J MED. CHEM(1986), 29—p. 1327-1329), which is incorporated by reference herein inits entirety. Its half life in water and at a pH of 4 is lower than 10minutes, being it of about 14 hours at a pH near 7.

Numerous alternatives have been explored to elaborate stablepharmaceutical forms mainly to solve the 2 most important problems (pHand moisture) affecting the stability of omeprazole. Thus, for example:

Britain patent GB No 2,189,698 (1987) describes the elaboration of anoral form of omeprazole characterized for having a core formed by theactive principle (omeprazole) with a basic reactant and said core iscoated by one or more protecting layers, which are water soluble, and anouter layer of enteric coating, which is incorporated herein byreference in its entirety. The proceeding and the obtained productsshowed an appropriate resistance to gastric fluid and a good stabilityof the active principle they contain (omeprazole) within gastric fluidand also when they are stored for a long period of time.

-   Phillips J. et al. have described a method for preparing omeprazole    suspensions using sodium bicarbonate and flavored for children    (Phillips J et al.—A prospective study of simplified omeprazole    suspension for the prophylaxis of stress-related mucosal damage.    Crit. Care Med 1996; 24:1793-800), which is incorporated herein by    reference in its entirety).

Before, in 1997 Quercia R. et al., demonstrated that it is possible toextemporaneously prepare a suspension with 2 mg/ml of omeprazole fororal use and which is stable for 14 days at 24° C. from capsulescontaining omeprazole granules with enteric coating and a solution ofsodium bicarbonate (Quercia R. et. al.—Stability of omeprazole in anextemporaneously prepared oral liquid—Vol. 54, Aug. 15, 1997, Am. J.Health—Syst. Pharm.—p. 1833, which is incorporated by reference hereinin its entirety).

WO 2005/007117 A2 (2005) describes a powder formulation for suspensioncontaining at least a soluble anti-acid, an inhibitor of the proton pumpand a suspension agent preferably xanthan gum, which is incorporated byreference herein in its entirety. This patent remarks the importance ofthe particle size of the proton pump inhibitor and the presence of thesuspension agent in the formulation in order to obtain a goodsuspendability. It is also noted that the presence of anti-acids in thecomposition increases the pH level of the gastrointestinal fluid, thusinhibiting the degradation of the proton pump inhibitor in the gastricenvironment.

EP 0813428 B1 (2002) describes a multi-particulate tablet compositioncontaining an inhibitor of proton pump along with alginate and one ormore anti-acid agents, which is incorporated by reference herein in itsentirety. The inhibitor of proton pump is under the form of pellets withenteric coating. This fact makes necessary the addition of a prior andspecific industrial stage for the elaboration of said pellets.

The above mentioned proceedings and most of those described by theliterature mention various conditions needed to assure the stability andefficiency of the inhibitor of proton pump. For example, priorelaboration of enteric pellets, micronization of the inhibitor, additionof suspendibility agents, addition of basic substances to the pellets,etc. All of them require industrial operations and additional equipment(micronizers, fluid bed, dryers, etc.) and generally a much moreextended time than the one necessary with the current proceedings forthe elaboration of the above described pharmaceutical forms.

The association of the present invention (sodium alginate, solubleanti-acid and inhibitor of proton pump) only uses the routine industrialequipment for the elaboration of pharmaceutical forms destined for oraladministration.

BRIEF DESCRIPTION OF THE INVENTION

The present invention refers to a new association for oral use and aproceeding for elaborating it containing sodium alginate, an inhibitorof proton pump and one or more soluble or partially soluble anti-acidsfor the treatment of hyperacidity and with immediate or long lastingactivity.

The anti-acid and the sodium alginate of the composition rapidlyneutralize hyperacidity acting directly in the digestive tract with noneed of prior absorption. The inhibitor of proton pump, prior absorptionat intestinal level, confers the pharmaceutical composition a prolongedcontrol of hyperacidity.

The proceeding for the elaboration of the association, object of thepresent invention, is mainly featured by 3 element of practicalimportance. Among them are:

1. Make a wet granulation of the inhibitor of proton pump with thetotality of the anti-acid agent or agents of the composition, otheringredients and up to 30% of the composition alginate, then proceedingto dry.

It is an objective of this operation to contribute with the beststability of the inhibitor of proton pump through the homogeneousdistribution of said inhibitor and part of the alginate of thecomposition (or internal alginate) over the surface of the anti-acidagent.

2. Afterwards mixing the above mentioned mixture with the rest of sodiumalginate present in the formulation and other ingredients thereof.

In order to favor the rapid dispersion of the remaining sodium alginateof the composition (or external alginate) and rapidly increase theviscosity of the solution or suspension when mixing the composition withwater prior to the intake.

3. Using, as external sodium alginate, specifically a sodium alginatecharacterized by its low molecular weight, granular structure and priordrying to an humidity of less than 2% in order to favor the rapidformation of an homogeneous suspension of all the ingredients of thecomposition after its reconstitution with water or other drink.Preferably, less than 2 minutes.

The election of the ingredients of the formulation and the elaborationprocess have shown that they allow to obtain compositions for oral usewith appropriate pharmaceutical and stability characteristics.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

Other advantages and characteristics of the invention will becomeevident from the following description in which, entirely fromnon-limitatively, are described some preferential embodiments of theinvention, with reference to the appended drawings. The figures show:

FIG. 1 is a microphotograph of a non-granulate mixture of sodiumbicarbonate-sodium alginate and omperazole;

FIG. 2 is a microphotograph of a granulate mixture of water and sodiumbicarbonate-sodium alginate and omperazole; and

FIG. 3 is a graph representing the behavior of the single dose granulatecontaining 20 mg of omeprazole.

DETAILED DESCRIPTION OF THE INVENTION

The industrial elaboration of a pharmaceutical composition in powderform destined to prepare, through dilution in water, a solution orsuspension capable to rapidly neutralize gastric hyperacidity, havinglong-lasting anti-acid activity and certain protective capacity ofgastric mucosa requires the presence of various ingredients withspecific functions and determined thereon.

The present invention demands the presence in the pharmaceuticalcomposition of:

1. An anti-acid which is soluble or partially-soluble in water:

The preferred ones are: Sodium or potassium bicarbonate, mixtures ofsodium bicarbonate and carbonate, sodium bicarbonate associated withcalcium and magnesium carbonate, sodium bicarbonate and calcium oraluminum hydroxide.

2. Alginic acid or its sodium or magnesium salts.

3. An inhibitor of proton pump:

The preferred among them are: omeprazole, esomeprazole, lansoprazole,pantoprazole and rabeprazole.

4. Besides of excipients, sugar, binder, scents, sweetener and the like.

The scents which are used during the present invention may be in powderform or coated (For example: Trademark Durarome by the company FIRMENICHor the like).

It has been shown through experiments that the mere mixture of theingredients of the composition is not enough for the elaboration of asuitable and stable pharmaceutical product.

The mere operation of mixing the ingredients leads to incorrectcompositions. Generally, they are characterized by:

1. Formation of precipitates due to irregular gelification of alginicacid or salts thereof.

2. Low fluidity of the powder through the product dosing and packagingstages.

3. Lack of uniformity of the contents of each dosing unit.

4. Irregular Distribution of the Inhibitor of proton pump over theanti-acid of the composition.

5. Irregular stability of the inhibitor of proton pump in acidenvironment upon the reconstitution of the pharmaceutical compositionwith water an prior to its administration.

6. In general, the pharmaceutical forms obtained upon reconstitutionwith water or other drinks are not homogeneous. Therefore, they are notconvenient for therapeutic use.

Surprisingly, it has been found and shown through experiments that it ispossible to elaborate, appropriately, with the same ingredients,powdered pharmaceutical forms to be reconstituted through the proceedingobject of the present invention.

The proceeding is original and requires various stages. They are:

A) Wet Granulation:

It involves

1) Mixing 100% of the inhibitor of proton pump in a Collette granulatoror similar, along with up to 30% of sodium alginate of the composition,100% of the bicarbonate of the composition, 100% of the mannitol of thecomposition at maximum speed over 3 cycles of 4 minutes each one at roomtemperature.

2) Wet the resulting mixture in the same granulator (e.g.: Collette) atminimum speed, adding water with a peristaltic pump over 1 minute, thenknead for 2 minutes at maximum speed. Using a total percentage in weightof water of no more than 10% of the total weight of the pharmaceuticalcomposition.

B) Dry the above mixture in fluid bed, under vacuum or under normalpressure:

At a temperature lower than 500 and until a residual humidity of 2% isobtained. Preferably lower than 0.7%.

C) Ground and homogenize the above dry granulate:

Using a Quadro Comill equipment with 991 micron conical sieve. Speed2400 rpm and in dry room.

D) At the same time, mix the remaining ingredients of the preparation:

In Double Cone mixer (Size 2) at 60 rpm during 30 minutes in a dry room.Final humidity, due to loss upon drying, should not be higher than 1.5%.

E) Finally:

a) After performing the wet granulation (A), drying (B), grinding andhomogenization (C), and mixing with the remaining ingredients (D).

b) Dose and package in an appropriate material.

c) Perform the following assessments: content of active principles,uniformity of the contents of the pharmaceutical composition andresidual humidity.

The enclosed photographs of electronic microscope allow for theobservation of the difference in homogenization and distributionbetween:

A physical mixture of the ingredients (Sodium alginate, Omeprazole ySodium bicarbonate) (FIG. 1) and,

The obtained granulate (and with the same ingredients) through the abovedescribe proceeding (FIG. 2).

The dosing and packaging of the composition, object of the presentinvention, may be performed, equally in:

A) Single dose Units, or either in

B) Multiple dose Units

In packages of 50-100 or 200 grams with airtight closure and attachedpowder metered-dose device. Corresponding to 10, 20 or 40 dosing units.One remarked and surprising aspect, due to its practical results, hasbeen the election of sodium alginate to be used for the presentinvention.

The alginic acid and its sodium salt are linear copolymers ofβ(1→4)-D-mannuronic acid and α-L-guluronic acid. They may have variablemorphologies and molecular weights. The molecular weight may rangebetween 20,000 and 200,000. Such characteristics confer each of themparticular properties.

Without being bond to theory, the sodium alginate used in the proceedingof this invention is characterized by having a low percentage ofhumidity of up to 2% per drying before the incorporation of thepreparation. Preferably 0.7%.

Most of commercial basic alginates and alginic acid have high humidity(8 to 15%) and their use is not convenient directly in the formulationobject of the present invention.

Besides, the content of sodium alginate of the pharmaceuticalcomposition should be lower than 20% of the total weight of theformulation. Preferably, between 2 and 10% of the total weight thereof.

The sodium alginate added to the composition, besides of its therapeuticactivity, supplies the composition with the following technicalcharacteristics:

During the granulation the presence of up to 30% of total sodiumalginate of the composition acts as a binder and notably improves thefluency of the mixture during the fractioning and packaging stages ofthe pharmaceutical product.

The binding property of alginates is well known and widely described intechnical literature. E.g.:

(Sakr A M, Elsabbagh H M, Shalaby A H, Effect of the technique ofincorporating sodium alginate on its binding and/or disintegratingeffectiveness in sulfathiazole tablets—PHARM IND. (1978); 40 (10);1080-1086), which is incorporated by reference herein in its entirety.

2) Also during wet granulation it favors the homogeneous distribution ofthe inhibitor of proton pump over the sodium bicarbonate and mannitol.

For the granulation state it is not necessary (although it isconvenient, due to its practical aspect) to use low humidity sodiumalginate.

3) The second fraction of sodium alginate of the total in thecomposition should preferably be of low humidity, which assures 3remarked characteristics:

a) Fast dissolution without the formation of clots or precipitatesduring the reconstitution of the powder in water. The practical use forthe pharmaceutical form for oral administration.

b) Rapid increase of viscosity of the solution or suspensionreconstituted with water. Favoring the homogeneous dispersion of theinhibitor of proton pump which is bond to the granulate crystals.

c) The rapid dispersion of sodium alginate (called “external”) and whichhas been incorporated after the wet granulation also favors theanti-acid and muco-protective activity of this substance over gastricmucosa.

Another surprising and experimentally demonstrated aspect has been thatwet granulation did not destroy the inhibitor of proton pump present inthe granulate. Even in the presence of water and at a temperature of upto 50° at normal pressure during a relatively considerable drying time.Possible due to the formation of a protecting basic micro-environmentgenerated by the sodium bicarbonate and the sodium alginate in intimatecontact with such inhibitor of proton pump. This protection has beendemonstrated and is mentioned in the Examples section.

It has also been indirectly demonstrated that the composition, due toits nature, protects the inhibitor of proton pump from gastric pH afterthe intake of the product for the time needed and enough to reach thefirst portion of the intestine, where the pH of the environment iscompatible with the chemical stability of said inhibitor.

Thus, for example:

It has been observed through experiments, and it is so described in theExamples section, that the composition object of the present inventionsuitably supports the incorporation of up to 20 mEq of hydrochloric acidduring 30 minutes (simulated gastric environment).

It has also been shown and it is so described in the Examples sectionthat the powder composition has convenient pharmaceutical stability andis suitable for human use under the form of extemporaneous suspensions.

It has been observed that the composition object of the presentinvention shows the following general characteristics and advantages:

1) When it is incorporated to a dosing unit at a volume of water of 30to 100 ml under stirring it forms a rapid and homogeneous suspension.

2) The low molecular weight sodium alginate, preferably granular andpreviously dried to a humidity of less than 2% is rapidly andpractically dispersed. It does not decant and contributes to anhomogeneous suspension of the inhibitor of proton pump and otheringredients.

3) When the composition is added to a simulated gastric environment:

a) A pH of more than 6 is reached in less than 2 minutes.

b) When 0.1N hydrochloric acid is incorporated afterwards at 0.66mEq/minute up to 20 mEquivalents, the pH is kept near 6 for about 30minutes. This is the time needed and enough for the inhibitor of protonpump to reach the first portion of the small intestine, as observed inthe Examples section below.

Figure C.

4) The stability of the inhibitor of proton pump is suitable, being,after 30 minutes higher than 95% and also 99%.

5) The addition of sodium alginate with the above mentionedcharacteristics gives certain flexibility to the formula:

a) It allows to modify the content of inhibitor of proton pump and otheringredients of the composition without altering neither itsphysical-chemical characteristics nor its stability.

b) And it meets, as mentioned above, 2 functions in the composition:

The addition of sodium alginate up to 30% added during the wetgranulation acts as a binder and improves flowability and uniformity ofthe contents of the composition, and possibly, along with the sodiumbicarbonate present in the wet granulation it protects the inhibitor ofproton pump.

The addition of the rest of sodium alginate up to 70% added afterwardsacts as gelification agent, anti-acid and protector of the gastricmucosa.

6) The thus obtained pharmaceutical forms, reconstituted with water orother drinks, are homogeneous and are, therefore, convenient for theirtherapeutic use in human medicine.

7) With the same composition it is possible to elaborate pharmaceuticalpresentations: Single dose and Multiple dose.

8) The flexibility of the proceeding allows to elaborate Single andMultiple dose compositions with a different content of inhibitor ofproton pump as required, for therapeutic reasons or due to the age ofpatients to whom the product is destined.

The following examples, without being limitating, show in practice thecompositions and the practical forms of elaboration.

EXAMPLE 1

Granulate in Single Dose Bags for Oral Suspension Using EncapsulatedScents (E 1)

Formula:

Each bag contains:

OMEPRAZOLE 20 mg SODIUM ALGINATE 50 mg MANNITOL 50 mg SODIUM BICARBONATE1680 mg  ANHYDROUS CORN STARCH 160 mg  DRIED SODIUM ALGINATE 200 mg ENCAPSULATED STRAWBERRY SCENT 75 mg ENCAPSULATED BANANA SCENT 75 mgSUCRALOSE 40 mg SUGAR GRADE q.s. 5000 mg 

Stages:

Stage I: Wet Granulation:

The granulate was prepared in an amount enough for 600 bags with:

OMEPRAZOLE 12 g SODIUM BICARBONATE 1008 g MANNITOL 30 g SODIUM ALGINATE30 g DISTILLED WATER (granulating 160 mg liquid)

Substances to be granulated were placed in a Collette granulator(omeprazole, sodium bicarbonate, mannitol y sodium alginate).

3 mixing runs were performed of 4 minutes each at maximum speed.

Distilled water was added through a peristaltic pump for 1 minute,granulating at minimum speed, and finally one run of mixing was appliedat maximum speed.

Stage II: Drying, Milling and Homogenization of the Granulate

The obtained wet granulate was dried in a fluid bed at 50° C. for 3hours until the residual humidity determined by loss upon drying wasbetween 0.5 and 1.5%.

The dry granulate was milled and homogenized in Quadro Comill Mill(sieve: 991 microns, speed: 2400 rpm).

The thus obtained granulate showed the following approximate particlesize distribution. Retained mesh 30 (600 microns) less than 1% Retainedmesh 140 (100 microns) more than 95%

Stage III: Mixing with the Other Ingredients of the Composition

Dried Sodium alginate: 100 grams of sodium alginate were first dried at70° C. under vacuum until a residual humidity of less than 2% wasobtained.

The dried omeprazole granulate obtained in stage II above (weight 1080g) was mixed with the following ingredients of the formulation:

DESICCATED SODIUM ALGINATE 120 g  CORN STARCH 96 g ENCAPSULATEDSTRAWBERRY SCENT 15 g ENCAPSULATED BANANA SCENT 15 g SUCRALOSE 24 gSUGAR 1650 g in Double Cone mixer tor 30 minutes at 60 rpm.

The dosage (in single dose bags) and final packaging was performed inRovena equipment using the appropriate foil: triple foil(paper-aluminum-polyethylene)

Content weight per bag: 5 g.

-   -   Humidity: 0.5 to 1.5%    -   Aqueous activity: 0.4 to 0.6% Rotronic hydroscop BT.    -   Approximate particle size distribution:

Retained mesh 30 (600 microns) less than 1%

Retained mesh 140 (100 microns) more than 95%

The dispersion of the content of a bag (5 g) in about 30 ml of water wasrapid, homogeneous and demanded less than 2 minutes.

The taste of the dispersion was good.

EXAMPLE 2 Granulate in Single Dose Bags Using Non-Encapsulated Scents(for Example: Strawberry-Banana) (E2)

The proceeding and ingredients stated in Example 1 were used, exceptthat the scents were not encapsulated. 600 bags were prepared.

Tests:

A) Corresponding to Intermediates Prepared According to Examples 1 and2, and from Stage I (Wet Granulation) and Stage II (Drying, Milling YHomogenization)

A1: Assay: Content of Omeprazole in Granulates Obtained According toExample I and Example II

Conditions:

Mobile phase: Acetonitrile: phosphate buffer

pH 7.2 (35.65)

Temperature: 25° C.

Flow rate: 1 ml/min.

Pressure: 1400 PSI

Reading wave length: 300 nm

Mean Area Response Factor Reference 1* 8918.7 0.000175 Reference 29791.4 *Omeprazole

Mean Area % omeprazole Weight (g) E 1 9149.92 100.72 1.81 E 2 8976.1299.42 1.8 E 1: Granulate of omeprazole ex. 1 E 2: Granulate ofomeprazole ex. 2

Samples were placed in a 25 ml volumetric flask and were brought tovolume with diluent*.

It was sonicated in a Test-Lab for 15 minutes, allowed to cool and thenit was magnetically stirred for 15 minutes.

One portion was filtered through nylon filter (0.45 μm) and a 2 in 10dilution was preformed with diluent*.

* Diluent: 0.01M Sodium borate—Acetonitrile (3:1).

A2: Stability of the Granulates with Omeprazole Obtained in Examples I Y2

Samples of both granulates were placed in caramel-colored bottles on thestove at 60° for 15 days.

The content of omeprazole was determined by HPLC:

Conditions:

Mobile phase: Acetonitrile: phosphate buffer

pH 7.2 (35.65)

Temperature: 25° C.

Flow rate: 1 ml/min.

Pressure: 1400 PSI

Reading Wave length 300 nm

% Omeprazole % Omeprazole (15 Sample (Time zero) days) Ex. 1 Granulate99.6 100.1 Ex. 2 Granulate 98.3 94.8

It was seen that under the wet granulation conditions, subsequent dryingat 50° C. and storage at 60° C./15 days, the stability of omeprazole andphysical appearance of the composition were satisfactory.

B) Corresponding to End Product (Granulate in Single Dose Bags for OralSuspension) Elaborated According to Stages 1, II and III Described inExamples 1 and 2).

B 1: Assay of the Granulates in Single Dose Bags for Oral Suspension

Conditions:

Mobile Phase Acetonitrile: phosphate buffer

pH 7.2 (35.65)

Temperature: 25° C.

Flow rate: 1 ml/min.

Pressure: 1400 PSI

Reading wave length: 300 nm

Mean Area Response Factor Reference 1* 5743.2 0.000418 Reference 25351.7 *Omeprazole

Mean Area % omeprazole Weight (g) Example 1 4914.8171 102.14 5.11Example 2 5109.0681 101.22 5.36

Ex. 1: Single dose Bag with Encapsulated Scents (Strawberry-Banana)

Ex. 2: Single dose Bag with Non-Encapsulated Scents (Strawberry-Banana)

Samples were placed in a 100 ml volumetric flask and 50 ml of diluentwere added*.

It is sonicated for 15 minutes, cooled and brought to volume withDiluent. It is magnetically stirred for 15 minutes and then filteredthrough nylon 0.45 μm.

* DILUENT: 0.01M Sodium borate-Acetonitrile (3:1).

B 2: Uniformity of the Content of Omeprazole in Granulates in SingleDose Bags for Oral Suspension:

The content of omeprazole is determined according to the above statedconditions.

Results were as follows:

Sample Mean Area Weight % omep. M1 4786.85 4.9886 99.1 M2 4793.07 4.9442100.1 M3 4846.00 5.0436 99.2 M4 4970.81 5.1499 99.7 M5 4700.41 4.896999.5 M6 4686.01 4.8263 100.2 M7 4736.74 5.0025 97.8 M8 4588.87 5.233090.5 M9 4627.41 4.8709 98.1  M10 4700.63 4.9078 98.9

AVERAGE: 98.34%

Variation coefficient: 2.89

M1 to M10: Correspond to bags with single dose granulate containingpowdered non-coated scents.

It is observed that the pharmaceutical composition obtained through theabove described elaboration proceeding has a very good uniformity ofomeprazole contents.

B 3: Behavior of the Single Dose Granulate in Bags for Oral SuspensionContaining 20 mg OF Omeprazole in Simulated Gastric Environment

a) The total content of one bag (5 g) dispersed in water was added to250 ml of 0.01 N HCl. Every 2 minutes (for a total of 30 minutes),addition of 0.1N hydrochloric acid was continued until the equivalent of20 mEq of HCl was completed, measuring the pH continuously.

It is observed that at 30 minutes the pH is near 6 and it allows to keepthe stability of the inhibitor of proton pump (omeprazole).

In FIG. 3: The change in pH is observed for the simulated gastricenvironment after the addition of the composition and throughout the 30minutes of addition of 0.1 N hydrochloric acid.

b) After 30 minutes samples were extracted from the assayed solution andthe content of omeprazole is determined (Method: HPLC according toExample II-C). The content was stable (99% of the starting amount ofomeprazole present in the bag).

EXAMPLE 3

Single Dose Granulate in Bags for Oral Suspension Containing,Respectively, 30 and 40 mg of Omeprazole

(A) (B) OMEPRAZOLE 30 mg 40 mg SODIUM BICARBONATE 1680 mg  1680 mg SODIUM ALGINATE 50 mg 50 mg DESICCATED SODIUM ALGINATE 200 mg  200 mg ANHYDROUS CORN STARCH 160 mg  160 mg  MANNITOL 50 mg 50 mg SUCRALOSE 40mg 40 mg BITTER CORRECTOR  4 mg  4 mg SUGAR q.s. 5000 mg  5000 mg LIME-LEMON SCENT 150 mg  150 mg  ORANGE-LEMON SCENT **** 150 mg 

600 bags were prepared of each strength (30 and 40 mg de omeprazole) andcontrolled according to Example 1 and 2 (stages I, II and III

EXAMPLE 4

Granulates in single dose bags were prepared for oral suspensionaccording to the product stated in Examples I and II, containing thefollowing inhibitors of proton pump: Lantoprazole, Esomeprazole andPantoprazole.

The single dose bag compositions for each inhibitor of the proton pumpare summarized in the following table:

Composition 1 2 3 4 5 6 7 8 9 PANTOPRAZOLE 20 **** **** 20 **** **** 40**** **** LANSOPRAZOLE **** 20 **** **** 30 **** **** 15 ****ESOMEPRAZOLE **** **** 20 **** **** 20 **** **** 40 SODIUM 1680 16801680 1680 1680 1680 1680 1680 1680 BICARBONATE SODIUM 50 50 50 50 50 5050 50 50 ALGINATE DESICCATED 200 200 200 200 200 200 200 200 200 SODIUMALGINATE DRY CORN 160 160 160 160 160 160 160 160 160 STARCH MANNITOL 5050 50 50 50 50 50 50 50 SUCRALOSE 40 40 40 40 40 40 40 40 40 SUGAR q.s.5000 5000 5000 5000 5000 5000 5000 5000 5000 LIME-LEMON 150 150 150 ******** **** **** **** **** ORANGE-LEMON **** **** **** 75 + 75 75 + 7575 + 75 **** **** **** BANANA- **** **** **** **** **** **** 75 + 7575 + 75 75 + 75 STRAWBERRY

The suspension in water showed, in all the cases, good and fresh taste.EXAMPLE 5

Granulate Multiple Dose Pharmaceutical Compositions for Oral Suspensionwhich Active Principle is Either: Omeprazole, Esomeprazole, Lansoprazoleor Pantoprazole

They were prepared according to the proceedings stated in Examples 1, IIand IV for multiple dose compositions.

Said compositions or granulates elaborated according to the above werepackaged in units (glass, high density polyethylene) and with air-tightclosure. Preferably, with threaded closure.

In every case, the addition was of:

a) One bag with desiccating material (Silicagel) to preserve thecontents of the humidity added during the packaging

b) One unit of powder measurement which allows patient to dose accordingto medical indication the granulate for oral suspension according to thedosage stated in every case (2.5 0 5.0 grams).

The multiple dose granulates showed an appropriate taste uponreconstitution in water and stability in time.

EXAMPLE 6

The proceeding stated in EXAMPLE 1 was used, replacing the sodiumbicarbonate (1680 mg) of the composition for an uniform mixtureconsisting of sodium bicarbonate (800 mg), potassium bicarbonate (700mg) and anhydrous sodium carbonate (150 mg).

600 units of granulate for oral use were prepared, and packaged insingle dose units.

One or more embodiments of the present invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. Anti-acid pharmaceutical composition for the rapid and prolongedneutralization of gastric acidity with mucosa-protecting activity inpowder form to prepare, by dispersion in water, a pharmaceuticalsolution or suspension for oral use CHARACTERIZED in that thecomposition comprises: sodium alginate; an anti-acid soluble agent or acombination of anti-acids; an inhibitor of proton pump; diluent andsweetening agents, wherein: a) up to 30% of sodium alginate present inthe formulation along with the total of the inhibitor of proton pump arehomogeneously distributed over the surface of the total solubleanti-acid agent or of the combination of anti-acids of the composition;and b) the rest of sodium alginate present in the formulation contains apercentage of humidity of less than 2%.
 2. A composition according toclaim 1, CHARACTERIZED in that it has a dispersion time in water of lessthan 2 minutes.
 3. A composition according to claim 1 CHARACTERIZED inthat the residual humidity of the pharmaceutical composition is lessthan 2% and preferably less than 0.7%.
 4. A composition according toclaim 1 CHARACTERIZED in that the sodium alginate of choice for thecomposition has a content of humidity of less than 2%, after drying. 5.A composition according to claim 1, CHARACTERIZED in that the inhibitorof proton pump is homogeneously distributed with part of the sodiumalginate over the surface of the soluble anti-acid agent or acombination of anti-acids remains stable at gastric pH for at least 30minutes.
 6. A composition according to claim 1 CHARACTERIZED by acontent of sodium alginate between 100 and 500 mg per dosage unit.
 7. Acomposition according to claim 1 CHARACTERIZED in that solubleanti-acids or combination of anti-acids are present between 100 and 2000mg per dosage unit.
 8. A composition according to claim 1 CHARACTERIZEDin that each dosage unit contains from 10 to 80 mg of inhibitor ofproton pump.
 9. A composition according to claim 5 CHARACTERIZED in thatthe inhibitor of proton pump is omeprazole, esomeprazole, pantoprazoleor lanzoprazole or the corresponding salts thereof.
 10. A compositionaccording to claim 1 CHARACTERIZED in that the anti-acid agent isselected from the group consisting of sodium or potassium bicarbonate,and mixtures thereof, associations of sodium bicarbonate and carbonate,sodium bicarbonate associated to calcium and magnesium carbonate, sodiumbicarbonate and calcium or aluminum hydroxide.
 11. A compositionaccording to claim 6 CHARACTERIZED in that each dosing unit contains 250mg of sodium alginate, 1680 mg of sodium bicarbonate as anti-acid agentand 20 mg of omeprazole.
 12. A composition according to claim 6CHARACTERIZED in that each dosage unit contains 250 mg of sodiumalginate, 1680 mg of sodium bicarbonate as anti-acid agent and 30 mg ofomeprazole.
 13. A composition according to claim 6 CHARACTERIZED in thateach dosage unit contains 250 mg of sodium alginate, 1680 mg of sodiumbicarbonate as anti-acid agent and 40 mg of omeprazole.
 14. Acomposition according to claim 6 CHARACTERIZED in that each dosage unitcontains 250 mg of sodium alginate, 1680 mg of sodium bicarbonate asanti-acid agent and 15 mg of lansoprazole.
 15. A composition accordingto claim 6 CHARACTERIZED in that each dosage unit contains 250 mg ofsodium alginate, 1680 mg of sodium bicarbonate as anti-acid agent and 30mg of lansoprazole.
 16. A composition according to claim 6 CHARACTERIZEDin that each dosage unit contains 250 mg of sodium alginate, 1680 mg ofsodium bicarbonate as anti-acid agent and 20 mg of esomeprazole.
 17. Acomposition according to claim 6 CHARACTERIZED in that each dosage unitcontains 250 mg of sodium alginate, 1680 mg of sodium bicarbonate asanti-acid agent and 40 mg of esomeprazole.
 18. A composition accordingto claim 6 CHARACTERIZED in that each dosage unit contains 250 mg ofsodium alginate, 1680 mg of sodium bicarbonate as anti-acid agent and 20mg of pantoprazole.
 19. A composition according to claim 6 CHARACTERIZEDin that each dosage unit contains 250 mg of sodium alginate, 1680 mg ofsodium bicarbonate as anti-acid agent and 40 mg of pantoprazole. 20.Pharmaceutical preparation in powder form, either single dose ormultiple dose, according to claim 1 CHARACTERIZED in that each dosageunit to be administered consists of 3 to 10 grams of the composition,preferably 5 grams.
 21. A pharmaceutical preparation according to claim20, CHARACTERIZED in that each dosage unit of 5 g of single dosegranulate for oral suspension contains 5 to 10% of sodium alginate,33.6% of sodium bicarbonate and 0.4 to 0.8% of inhibitor of proton pump.22. A process for preparing a composition according to claim 1CHARACTERIZED in that the process comprises: a) mixing the totality ofthe soluble anti-acid agent or combination of anti-acids of thecomposition, the total of the inhibitor of proton pump and up to 30% ofsodium alginate of the composition are mixed until the mixture ishomogeneous at room temperature, in a convenient granulator; b)impregnate the mixture of such ingredients with water in the samegranulator then adding a total weight of pharmaceutical composition; c)dry the thus obtained mixture at normal pressure, under vacuum or fluidbed at a temperature of less than 50° C. until the residual humidity isless than 2%; d) to the granulate obtained in stage (c) above,incorporate the rest of sodium alginate of the composition andingredients of the formula, also sieved, and with an humidity of lessthan 2% and mix for 30 minutes; e) check that the residual humidity ofthe composition is less than 2%; and f) dose and package.
 23. Acomposition according to claim 3 CHARACTERIZED in that the residualhumidity of the pharmaceutical composition is less than 0.7%.
 24. Acomposition according to claim 6 CHARACTERIZED by a content of sodiumalginate of 250 mg per dosage unit.
 25. Pharmaceutical preparation inpowder form, either single dose or multiple dose, according to claim 20CHARACTERIZED in that each dosage unit to be administered consists of 5grams of the composition.
 26. The process according to claim 22,CHARACTERIZED by e) check that the residual humidity of the compositionis less than 0.7%.